The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory

Abstract

Female mammals undergo natural fluctuations in sex steroid hormone levels throughout life. These fluctuations span from early development, to cyclic changes associated with the menstrual or estrous cycle and pregnancy, to marked hormone flux during perimenopause, and a final decline at reproductive senescence. While the transition to reproductive senescence is not yet fully understood, the vast majority of mammals experience this spontaneous, natural phenomenon with age, which has broad implications for long-lived species. Indeed, this post-reproductive life stage, and its transition, involves significant and enduring physiological changes, including considerably altered sex steroid hormone and gonadotropin profiles that impact multiple body systems, including the brain. The endocrine-brain-aging triad is especially noteworthy, as many paths meet and interact. Many of the brain regions affected by aging are also sensitive to changes in ovarian hormone levels, and aging and reproductive senescence are both associated with changes in memory performance. This review explores how menopause is related to cognitive aging, and discusses some of the key neural systems and molecular factors altered with age and reproductive hormone level changes, with an emphasis on brain regions important for learning and memory.

Sex Hormones and Cognitive Functions: Current Data

“…Уровни гонадотропина, в том числе ЛГ и ФСГ, также связаны с когнитивными функциями и влияют на их снижение [29,30]. Эндогенный ЛГ может регулировать обучение и память через рецепторы ЛГ, которые были идентифицированы в когнитивно значимых областях мозга, таких как гиппокамп [31], или косвенно через способность эстрогена регулировать активность ЛГ [29]. Меньше исследований проведено по изучению связи между ФСГ и когнитивными функциями.…”

“…Доказано, что уровень гонадотропинов, особенно ЛГ, играет роль в снижении когнитивных функций [29,30,87]. В постменопаузу снижение уровня эстрогенов приводит к увеличению выработки ЛГ.…”

Menopause and illness course in bipolar disorder: A systematic review

“…Physical symptom severity and changes in subjective measures of wellbeing may also be associated with age of onset of menopause, with earlier onset being associated with greater physical symptom severity and poorer psychosocial functioning . Many areas of the brain related to aging may also be sensitive to changes in hormonal levels, with gonadal changes that occur around mid‐life also being thought to be associated with changes in cognitive functioning …”

“…4 Many areas of the brain related to aging may also be sensitive to changes in hormonal levels, with gonadal changes that occur around mid-life also being thought to be associated with changes in cognitive functioning. 5 Mood symptoms are known to be common throughout the menopause transition period. 6,7 A recent meta-analysis of 11 studies reported a greater risk of depressive symptoms during perimenopause compared to pre-menopause phases, with further analysis also finding greater symptom severity.…”

Sex Hormones and Alzheimer’s Disease

“…Estrogens also improve neuronal plasticity especially in the hippocampus, increase cerebral blood flow by enhancing endothelial derived nitric oxide and prostacyclin pathways, regulate neural mitochondrial functions (both types of ER are expressed in the mitochondria) especially in stressful conditions by stimulating anti-apoptotic proteins and decrease free radical production. At the same time, estrogen exerts anti-inflammatory actions by reducing the expression of astrocyte to chemokines, promoting the maturation of oligodendrocyte precursor cells and improve their ability for CNS repair, which enhances the growth and differentiation of axons and dendrites and prevents axonal loss and demyelination [46].…”